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Progesterone receptor
The progesterone receptor is an intracellular steroid receptor that specifically binds progesterone. Expressed by a single gene (chromosome 11q22), it has two main forms, A and B, that differ in their molecular weight. Structure Like all steroid receptors, the progesterone receptor has an amino acid and a carboxyl terminal, and between them the regulatory domain, a DNA binding domain, the hinge section, and the hormone binding domain. A special transcription activation function (TAF), called TAF-3, is present in the progesterone receptor-B, in a B-upstream segment (BUS) at the amino acid terminal. This segment is not present in the receptor-A. Isoforms As demonstrated in progesterone receptor-deficient mice, the physiological effects of progesterone depend completely on the presence of the human progesterone receptor (hPR), a member of the steroid-receptor superfamily of nuclear receptors. The single-copy human (hPR) gene uses separate promoters and translational start sites to produce two isoforms, hPR-A and -B, which are identical except for an additional 165 amino acids present only in the N terminus of hPR-B (Chambone 1980). Although hPR-B shares many important structural domains as hPR-A, they are in fact two functionally distinct transcription factors, mediating their own response genes and physiological effects with little overlap. Selective ablation of PR-A in a mouse model, resulting in exclusive production of PR-B, unexpectedly revealed that PR-B contributes to, rather than inhibits, epithelial cell proliferation both in response to estrogen alone and in the presence of progesterone and estrogen. These results suggest that in the uterus, the PR-A isoform is necessary to oppose estrogen-induced proliferation as well as PR-B-dependent proliferation. Considering the overwhelming epidemiological evidence of the role of estrogen and progesterone in endometrial cancer causation, and the biological data demonstrating the selective contributions of the individual PR isoforms to endometrial hyperplasia (De Vivo 2001). Functional Polymorphisms The Immaculata De Vivo laboratory at the Harvard Medical School has identified six variable sites, including four polymorphisms in the hPR gene and five common haplotypes. One promoter region polymorphism, +331G/A, creates a unique transcription start site. Biochemical assays showed that the +331G/A polymorphism increases transcription of the PR gene, favoring production of hPR-B in an Ishikawa endometrial cancer cell line. Using a case-control study nested within the Nurses' Health Study cohort, the De Vivo research group observed a statistically significant association between the +331G/A polymorphism and the risk of endometrial cancer, which was even greater in overweight women carriers. After including a second population of controls, these associations remained intact. These findings suggest that the +331G/A hPR gene polymorphism may contribute to endometrial cancer risk by increasing expression of the hPR-B isoform. In vitro studies performed by the De Vivo laboratory have demonstrated tissue specificity in the functionality of the +331G/A polymorphism. In breast cancer cell lines, the interaction of GATA5 transcription factor is required in synergy with the +331A genotype in order to favor production of the hPR-B isoform (Huggins, De Vivo, Wong, Hankinson 2006). Function Estrogen is necessary to induce the progesterone receptors. When no binding hormone is present the carboxyl terminal inhibits transcription. Binding to a hormone induces a structural change that removes the inhibitory action. Progesterone antagonists prevent the structural reconfiguration. After progesterone binds to the receptor, restructuring with dimerization follows and the complex enters the nucleus and binds to DNA. There transcription takes place, resulting in formation of messenger RNA that activates cytoplasmatic ribosomes to produce specific proteins. See also * Selective progesterone receptor modulator Reference Speroff L, Glass RH, Kase NG: Clinical Gynecologic Endocrinology and Infertility. Sixth Ed. Lippincott Williams & Wilkins, Baltimore,MD, 1999. External links * Category:Intracellular receptors fr:récepteur de la progestérone